Wednesday, September 18, 2013

The Bacterium Behind Colon Cancer

Today I wrote a post for BigThink that I've been meaning to write for weeks. In August, several papers were published showing that a particular bacterium, Fusobacterium nucleatum, is strongly implicated in development of colorectal cancer (CRC).

Fusobacterium living in intestinal mucosa.

The latest research in no way invalidates the huge existing body of work showing strong (almost certainly causal) connections between CRC and consumption of alcohol, sugar, meat, and/or tobacco. There are other risk factors as well, such as lack of physical activity (by itself), obesity, and genetics. (See this paper and this one for more discussion, and by all means do further investigation on your own using Google Scholar.) Genetic susceptibility, however, plays a role in no more than about 5% of CRC cases. (And even in those cases, it's by no means certain that bad alleles constitute a death sentence.)

The picture that's emerging is a complex one in which intestinal dysbiosis triggered by (for example) poor eating habits leads to the differential accumulation of various species of gut bacteria (Bacteroides fragilis, Fusobacterium nucleatum, and others) that are implicated in colorectal cancer. At some point (over a period of years, apparently), Fusobacterium gains entry to intestinal muscosal cells. (F. nucleatum has aspects of an intracellular-parasitic lifestyle.) Once it has established residency, F. nucleatum overproduces FadA adhesin, a small protein containing 129 amino acids, the exact sequence for which (in FASTA format) is:

The letters here correspond to amino acids, using the standard one-letter code system (as presented here). In three dimensions, the FadA protein looks something like this:

Your new worst enemy: FadA adhesin produced by Fusobacterium nucleatum, the "kickoff protein" for colon cancer.

When this relatively small protein binds with normal E-adhesin (in a specific 11-amino-acid region), it activates β-catenin signaling, which in turn unleashes a cascade of cytokines (cytokines IL-6, IL-10, IL-12, IL-17, plus TNF-α) and an inflammatory cycle that leads straight to adenoma of the colon.

Now the really interesting thing about F nucleatum is that it's most commonly found not in the large intestine but in your mouth. Which brings up some interesting questions, right? For example: How does poor oral hygiene correlate with colorectal cancer? Little work has been done on that specific connection, but a huge amount of work has been (and continues to be) done on the substantial and increasingly obvious link between periodontal disease and cancer in general (which I'll probably blog about at some future time).

If the link between F. nucleatum's FadA protein and CRC proves to be as solid as it's starting to look, it opens countless doors to new therapeutic approaches to CRC treatment and prevention. We need to know, for example, if specific probiotic treatments can greatly reduce the risk of precancerous adenomas by staving off dysbiosis. We also urgently need to know if the outlook for early-stage CRC patients can be improved with aggressive use of antibiotics, including antibiotic-induced near-sterilization of the large intestine followed by fecal transplantation to restore the normal flora.

It hardly needs mentioning, but if it turns out to be true that CRC is mainly a result of a single bacterium, perhaps a vaccine can be developed, either against Fusobacterium or against the FadA protein, or both.

I'm extremely encouraged by the recent research pinpointing FadA as the likely culprit in CRC. Obviously, much work remains to be done. But we have an exciting new insight into this particular type of carcinogenesis. The treatment options that come out of it may well lead to other cures.

Some of us (here I'm speaking with my microbiologist's hat on; I have an advanced degree in the subject) have long suspected that microbes play a role in fostering—and preventing—various cancers. When I was in graduate school, you could count the number of microbially caused neoplasms on your thumbs. Now you have to use most fingers of both hands. Who knows what the full truth may yet turn out to be?

Exciting times. If you enjoyed this post, or the corresponding one at BigThink, do me a favor. Tweet it or share it in some fashion. This is knowledge that deserves to get out. Who knows? It may save a life.